Cyclin dependent kinase 5 (CdkS) is a protein ser/thr kinase that is highly expressed in post-mitotic neurons. CdkS is inactive unless it is associated with a regulatory activator. Two related neuron-specific proteins, p35 and p39, have been identified that activate CdkS upon direct binding. In the past decade, CdkS and its activators have been identified as essential regulators of cytoarchitecture and axon guidance in the developing nervous system. Recent data also suggests a role for CdkS in synaptic plasticity, learning and memory. Interestingly, there is also substantial evidence supporting the involvement of CdkS in neurodegeneration. In the past grant period, we demonstrated that the conversion of p35 to p25, through cleavage by the cysteine protease calpain under neurotoxic conditions, leads to prolonged activation and mislocalization of CdkS. Several lines of evidence further suggest a link between p25, CdkS and Alzheimer's disease (AD) including the increased p25 levels in postmortem AD brain samples and the phosphorylation of tau on the PHF sites detected in neurofibrillary tangles. Recently, we have created inducible p25 transgenic (CK-p25 Tg) mice that specifically express p25 in the postnatal forebrain. We reported that these mice exhibit profound neurodegeneration, including massive neuronal loss and tau associated pathology. Unexpectedly, we also found that the IJ-amyloid (AR) peptides are upregulated prior to neurodegeneration in these mice. These observations support a role for the deregulation of CdkS in the progression of Alzheimer's disease. There are 3 specific aims in this application. 1. To decipher the mechanism by which Abeta peptides are upregulated in the CK-p25 Tg mice. 2. To determine how p25 causes aberrant synaptic properties and impaired learning behavior. 3. To investigate the function of CASK phosphorylation by CdkS in normal synaptic function and neurodegeneration. These experiments should provide insight into the mechanism linking disruption of synaptic functions and neurodegenerative diseases. [unreadable] [unreadable]